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OBJECTIVE: To evaluate associations between plasma biomarkers of brain injury and MRI and cognitive measures in participants with type 1 diabetes (T1D) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. RESEARCH DESIGN AND METHODS: Plasma amyloid-ß-40, amyloid-ß-42, neurofilament light chain (NfL), phosphorylated Tau-181 (pTau-181), and glial fibrillary acidic protein (GFAP) were measured in 373 adults who participated in the DCCT/EDIC study. MRI assessments included total brain and white matter hyperintensity volumes, white matter mean fractional anisotropy, and indices of Alzheimer disease (AD)-like atrophy and predicted brain age. Cognitive measures included memory and psychomotor and mental efficiency tests and assessments of cognitive impairment. RESULTS: Participants were 60 (range 44-74) years old with 38 (30-51) years' T1D duration. Higher NfL was associated with an increase in predicted brain age (0.51 years per 20% increase in NfL; P < 0.001) and a 19.5% increase in the odds of impaired cognition (P < 0.01). Higher NfL and pTau-181 were associated with lower psychomotor and mental efficiency (P < 0.001) but not poorer memory. Amyloid-ß measures were not associated with study measures. A 1% increase in mean HbA1c was associated with a 14.6% higher NfL and 12.8% higher pTau-181 (P < 0.0001). CONCLUSIONS: In this aging T1D cohort, biomarkers of brain injury did not demonstrate an AD-like profile. NfL emerged as a biomarker of interest in T1D because of its association with higher HbA1c, accelerated brain aging on MRI, and cognitive dysfunction. Our study suggests that early neurodegeneration in adults with T1D is likely due to non-AD/nonamyloid mechanisms.
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OBJECTIVE: Hearing loss has been identified as a major modifiable risk factor for cognitive decline. The Early Age-Related Hearing Loss Investigation (EARHLI) study will assess the mechanisms linking early age-related hearing loss (ARHL) and cognitive impairment. STUDY DESIGN: Randomized, controlled, single-site, early phase II, superiority trial. SETTING: Tertiary academic medical center. PARTICIPANTS: One hundred fifty participants aged 55 to 75 years with early ARHL (severity defined as borderline to moderate) and amnestic mild cognitive impairment will be included. INTERVENTIONS: Participants will be randomized 1:1 to a best practice hearing intervention or a health education control. MAIN OUTCOME MEASURES: The primary study outcome is cognition measured by the Alzheimer Disease Cooperative Study-Preclinical Alzheimer Cognitive Composite. Secondary outcomes include additional measures of cognition, social engagement, and brain organization/connectivity. RESULTS: Trial enrollment will begin in early 2024. CONCLUSIONS: After its completion in 2028, the EARHLI trial should offer evidence on the effect of hearing treatment versus a health education control on cognitive performance, social engagement, and brain organization/connectivity in 55- to 75-year-old community-dwelling adults with early ARHL and amnestic mild cognitive impairment.
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Disfunção Cognitiva , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Perda Auditiva , PresbiacusiaRESUMO
BACKGROUND: Allostatic load (AL) has been studied in the context of biomarkers that may be affected by environmental and contextual stressors, including social determinants of health. The specific stressor studied here is the provision of caregiving to older persons with Alzheimer disease and related disorders. The aims were to examine the factor structure of stress and nonstress biomarkers, different methods for calculating AL, and the relationship of AL with other variables. METHODS: Latent variable models were used to examine biomarkers. Regression analyses were performed with the outcomes: AL calculated as percentile-based and clinically-based for both stress and nonstress components. The sample was 187 Hispanic caregivers to individuals with dementia. RESULTS: The results of the confirmatory factor analyses (CFAs) suggested defining 2 factors: nonstress and stress-related. Performance was better for the CFA results and the associations with covariates when stress and nonstress components were examined separately. Despite some limitations, this is one of the first studies of biomarkers in Hispanic caregivers to patients with dementia. It was possible to explain almost 30% of the variance in the nonstress AL component. CONCLUSION: It may be important to differentiate among biomarkers indicative of cardiovascular, metabolic, and immune response as contrasted with the more stress-related biomarkers.
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Alostase , Doença de Alzheimer , Biomarcadores , Cuidadores , Hispânico ou Latino , Estresse Psicológico , Humanos , Cuidadores/psicologia , Alostase/fisiologia , Masculino , Feminino , Hispânico ou Latino/estatística & dados numéricos , Hispânico ou Latino/psicologia , Idoso , Biomarcadores/sangue , Pessoa de Meia-Idade , AdultoRESUMO
Importance: Nursing home (NH) transfers to hospitals are common and have been associated with cognitive decline; approximately 45% of NH hospital transfers are potentially avoidable hospitalizations (PAHs). Objective: To determine PAH incidence for historically marginalized NH residents with severe cognitive impairment compared with non-Hispanic White residents. Design, Setting, and Participants: This cross-sectional study merged 2018 Centers for Medicaid & Medicare Services datasets and LTCFocus, a public dataset on US NH care, for US NH residents aged 65 years and older who had a hospitalization. Analyses were performed from January to May 2022. Exposure: Race and ethnicity of NH residents. Main Outcomes and Measures: Racial and ethnic differences in resident-level annual rates of PAHs were estimated for residents with and without severe cognitive impairment (measured using the Cognitive Function Scale), controlling for resident characteristics, comorbidities, dual eligibility, and time at risk. PAHs were defined as NH hospital transfers that resulted from neglectful NH care or for which NH treatment would have been appropriate. Results: Of 2â¯098â¯385 NH residents nationwide included in the study, 7151 (0.3%) were American Indian or Alaska Native, 39â¯873 (1.9%) were Asian, 229â¯112 (10.9%) were Black or African American, 99â¯304 (4.7%) were Hispanic, 2785 (0.1%) were Native Hawaiian or Pacific Islander, 1â¯713â¯670 (81.7%) were White, and 6490 (0.3%) were multiracial; 1â¯355â¯143 (64.6%) were female; 128â¯997 (6.2%) were severely cognitively impaired; and the mean (SD) age was 81.8 (8.7) years. PAH incidence rate ratios (IRRs) were significantly greater for residents with severe cognitive impairment compared with those without. In unadjusted analyses comparing historically marginalized residents with severe cognitive impairment vs non-Hispanic White residents with severe cognitive impairment, American Indian or Alaska Native residents had a 49% higher PAH incidence (IRR, 1.49 [95% CI, 1.10-2.01]), Black or African American residents had a 64% higher incidence (IRR, 1.64 [95% CI, 1.48-1.81]), and Hispanic residents had a 45% higher incidence (IRR, 1.45 [95% CI, 1.29-1.62]). Higher incidences persisted for historically marginalized residents with severe cognitive impairment vs non-Hispanic White residents with severe cognitive impairment in adjusted analyses. Asian residents had a 24% higher PAH incidence (IRR, 1.24 [95% CI, 1.06-1.45]), Black or African American residents had a 48% higher incidence (IRR, 1.48 [95% CI, 1.36-1.60]), and Hispanic residents had a 27% higher incidence (IRR, 1.27 [95% CI, 1.16-1.39]). Conclusions and Relevance: In this cross-sectional study of PAHs, compared with non-Hispanic White NH residents, historically marginalized residents had increased PAH incidence. In the presence of severe cognitive impairment, incidence rates increased significantly compared with rates for residents without severe cognitive impairment. These results suggest that identification of residents with severe cognitive impairment and proper NH care may help prevent further cognitive decline by avoiding PAHs.
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Hospitalização , Casas de Saúde , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/etnologia , Estudos Transversais , Hospitalização/estatística & dados numéricos , Casas de Saúde/estatística & dados numéricos , Transferência de Pacientes/estatística & dados numéricos , Estados Unidos/epidemiologia , População Branca/estatística & dados numéricos , Brancos , Hispânico ou Latino , Indígena Americano ou Nativo do Alasca , Asiático , Negro ou Afro-Americano , Havaiano Nativo ou Outro Ilhéu do Pacífico , Grupos RaciaisRESUMO
BACKGROUND: Benfotiamine provides an important novel therapeutic direction in Alzheimer's disease (AD) with possible additive or synergistic effects to amyloid targeting therapeutic approaches. OBJECTIVE: To conduct a seamless phase 2A-2B proof of concept trial investigating tolerability, safety, and efficacy of benfotiamine, a prodrug of thiamine, as a first-in-class small molecule oral treatment for early AD. METHODS: This is the protocol for a randomized, double-blind, placebo-controlled 72-week clinical trial of benfotiamine in 406 participants with early AD. Phase 2A determines the highest safe and well-tolerated dose of benfotiamine to be carried forward to phase 2B. During phase 2A, real-time monitoring of pre-defined safety stopping criteria in the first approximately 150 enrollees will help determine which dose (600 mg or 1200 mg) will be carried forward into phase 2B. The phase 2A primary analysis will test whether the rate of tolerability events (TEs) is unacceptably high in the high-dose arm compared to placebo. The primary safety endpoint in phase 2A is the rate of TEs compared between active and placebo arms, at each dose. The completion of phase 2A will seamlessly transition to phase 2B without pausing or stopping the trial. Phase 2B will assess efficacy and longer-term safety of benfotiamine in a larger group of participants through 72 weeks of treatment, at the selected dose. The co-primary efficacy endpoints in phase 2B are CDR-Sum of Boxes and ADAS-Cog13. Secondary endpoints include safety and tolerability measures; pharmacokinetic measures of thiamine and its esters, erythrocyte transketolase activity as blood markers of efficacy of drug delivery; ADCS-ADL-MCI; and MoCA. CONCLUSION: The BenfoTeam trial utilizes an innovative seamless phase 2A-2B design to achieve proof of concept. It includes an adaptive dose decision rule, thus optimizing exposure to the highest and best-tolerated dose. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT06223360, registered on January 25, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT06223360.
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Doença de Alzheimer , Tiamina , Humanos , Doença de Alzheimer/tratamento farmacológico , Tiamina/análogos & derivados , Tiamina/uso terapêutico , Tiamina/administração & dosagem , Tiamina/efeitos adversos , Método Duplo-Cego , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Resultado do Tratamento , Pró-Fármacos/efeitos adversos , Pró-Fármacos/uso terapêutico , Pró-Fármacos/administração & dosagem , Pró-Fármacos/farmacocinéticaRESUMO
OBJECTIVE: Dysglycemia is a significant risk factor for cognitive impairment. However, which pathophysiologic determinant(s) of dysglycemia, impaired insulin sensitivity (ISens) or the islet ß-cell's response (IResp), contribute to poorer cognitive function, independent of dysglycemia is not established. Among 1052 adults with pre-diabetes from the Diabetes Prevention Program Outcomes Study (DPPOS), we investigated the relationship between IResp, ISens and cognitive function. RESEARCH DESIGN AND METHODS: IResp was estimated by the insulinogenic index (IGI; pmol/mmol) and ISens as 1/fasting insulin from repeated annual oral glucose tolerance tests. The mean IResp and mean ISens were calculated over approximately 12 years of follow-up. Verbal learning (Spanish-English Verbal Learning Test [SEVLT]) and executive function (Digital Symbol Substitution Test [DSST]) were assessed at the end of the follow-up period. Linear regression models were run for each cognitive outcome and were adjusted for dysglycemia and other factors. RESULTS: Higher IResp was associated with poorer performance on the DSST (-0.69 points per 100 unit increase in IGI, 95 % CI: -1.37, -0.01). ISens was not associated with DSST, nor were IResp or ISens associated with performance on the SEVLT. CONCLUSIONS: These results suggest that a greater ß-cell response in people at high risk for type 2 diabetes is associated with poorer executive function, independent of dysglycemia and ISens.
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Diabetes Mellitus Tipo 2 , Resistência à Insulina , Insulina , Estado Pré-Diabético , Humanos , Estado Pré-Diabético/psicologia , Estado Pré-Diabético/complicações , Estado Pré-Diabético/sangue , Estado Pré-Diabético/epidemiologia , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Insulina/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/psicologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/prevenção & controle , Cognição/fisiologia , Teste de Tolerância a Glucose , Células Secretoras de Insulina/fisiologia , Células Secretoras de Insulina/metabolismo , Seguimentos , Transtornos Cognitivos/prevenção & controle , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/epidemiologia , Transtornos Cognitivos/sangue , Idoso , Função Executiva/fisiologiaRESUMO
BACKGROUND AND AIMS: Subclinical cardiovascular disease (CVD) measures may reflect biological pathways that contribute to increased risk for coronary heart disease (CHD) events, stroke, and dementia beyond conventional risk scores. METHODS: The Multi-Ethnic Study of Atherosclerosis (MESA) followed 6814 participants (45-84 years of age) from baseline in 2000-2002 to 2018 over 6 clinical examinations and annual follow-up interviews. MESA baseline subclinical CVD procedures included: seated and supineblood pressure, coronary calcium scan, radial artery tonometry, and carotid ultrasound. Baseline subclinical CVD measures were transformed into z-scores before factor analysis to derive composite factor scores. Time to clinical event for all-cause CVD, CHD, stroke and ICD code-based dementia events were modeled using Cox proportional hazards models reported as area under the curve (AUC) with 95% Confidence Intervals (95%CI) at 10 and 15 years of follow-up. All models included all factor scores together, and adjustment for conventional risk scores for global CVD, stroke, and dementia. RESULTS: After factor selection, 24 subclinical measures aggregated into four distinct factors representing: blood pressure, atherosclerosis, arteriosclerosis, and cardiac factors. Each factor significantly predicted time to CVD events and dementia at 10 and 15 years independent of each other and conventional risk scores. Subclinical vascular composites of atherosclerosis and arteriosclerosis best predicted time to clinical events of CVD, CHD, stroke, and dementia. These results were consistent across sex and racial and ethnic groups. CONCLUSIONS: Subclinical vascular composites of atherosclerosis and arteriosclerosis may be useful biomarkers to inform the vascular pathways contributing to events of CVD, CHD, stroke, and dementia.
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Demência , Acidente Vascular Cerebral , Humanos , Idoso , Feminino , Masculino , Demência/etnologia , Demência/epidemiologia , Demência/diagnóstico , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Acidente Vascular Cerebral/etnologia , Acidente Vascular Cerebral/epidemiologia , Medição de Risco , Estados Unidos/epidemiologia , Fatores de Risco , Doenças Cardiovasculares/etnologia , Doenças Cardiovasculares/diagnóstico , Aterosclerose/etnologia , Aterosclerose/diagnóstico , Doenças Assintomáticas , Valor Preditivo dos Testes , Estudos Prospectivos , Fatores de Tempo , PrognósticoRESUMO
Background: Histopathologic studies of Alzheimer's disease (AD) suggest that extracellular amyloid-ß (Aß) plaques promote the spread of neurofibrillary tau tangles. However, these two proteinopathies initiate in spatially distinct brain regions, so how they interact during AD progression is unclear. Objective: In this study, we utilized Aß and tau positron emission tomography (PET) scans from 572 older subjects (476 healthy controls (HC), 14 with mild cognitive impairment (MCI), 82 with mild AD), at varying stages of the disease, to investigate to what degree tau is associated with cortical Aß deposition. Methods: Using multiple linear regression models and a pseudo-longitudinal ordering technique, we investigated remote tau-Aß associations in four pathologic phases of AD progression based on tau spread: 1) no-tau, 2) pre-acceleration, 3) acceleration, and 4) post-acceleration. Results: No significant tau-Aß association was detected in the no-tau phase. In the pre-acceleration phase, the earliest stage of tau deposition, associations emerged between regional tau in medial temporal lobe (MTL) (i.e., entorhinal cortex, parahippocampal gyrus) and cortical Aß in lateral temporal lobe regions. The strongest tau-Aß associations were found in the acceleration phase, in which tau in MTL regions was strongly associated with cortical Aß (i.e., temporal and frontal lobes regions). Strikingly, in the post-acceleration phase, including 96% of symptomatic subjects, tau-Aß associations were no longer significant. Conclusions: The results indicate that associations between tau and Aß are stage-dependent, which could have important implications for understanding the interplay between these two proteinopathies during the progressive stages of AD.
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Doença de Alzheimer , Disfunção Cognitiva , Deficiências na Proteostase , Humanos , Proteínas tau/metabolismo , Peptídeos beta-Amiloides/metabolismo , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Lobo Temporal/patologia , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/patologia , Tomografia por Emissão de Pósitrons/métodosRESUMO
Retinal vessel calibers share anatomic and physiologic characteristics with the cerebral vasculature and can be visualized noninvasively. In light of the known microvascular contributions to brain health and cognitive function, we aimed to determine if, in a community based-study, retinal vessel calibers and change in caliber over 8 years are associated with cognitive function or trajectory. Participants in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort who completed cognitive testing at Exam 5 (2010-2012) and had retinal vascular caliber measurements (Central Retinal Artery and Vein Equivalents; CRAE and CRVE) at Exam 2 (2002-2004) and Exam 5 were included. Using multivariable linear regression, we evaluated the association of CRAE and CRVE from Exam 2 and Exam 5 and their change between the two exams with scores on tests of global cognitive function (Cognitive Abilities Screening Instrument; CASI), processing speed (Digit Symbol Coding; DSC) and working memory (Digit Span; DS) at Exam 5 and with subsequent change in cognitive scores between Exam 5 and Exam 6 (2016-2018).The main effects are reported as the difference in cognitive test score per SD increment in retinal vascular caliber with 95% confidence intervals (CI). A total of 4334 participants (aged 61.6 ± 9.2 years; 53% female; 41% White) completed cognitive testing and at least one retinal assessment. On multivariable analysis, a 1 SD larger CRAE at exam 5 was associated with a lower concomitant CASI score (- 0.24, 95% CI - 0.46, - 0.02). A 1 SD larger CRVE at exam 2 was associated with a lower subsequent CASI score (- 0.23, 95%CI - 0.45, - 0.01). A 1 SD larger CRVE at exam 2 or 5 was associated with a lower DSC score [(- 0.56, 95% CI - 1.02, - 0.09) and - 0.55 (95% CI - 1.03, - 0.07) respectively]. The magnitude of the associations was relatively small (2.8-3.1% of SD). No significant associations were found between retinal vessel calibers at Exam 2 and 5 with the subsequent score trajectory of cognitive tests performance over an average of 6 years. Wider retinal venular caliber was associated with concomitant and future measures of slower processing speed but not with later cognitive trajectory. Future studies should evaluate the utility of these measures in risk stratification models from a clinical perspective as well as for screening on a population level.
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Aterosclerose , Artéria Retiniana , Humanos , Feminino , Masculino , Vasos Retinianos , Retina , Aterosclerose/epidemiologia , Cognição , Fatores de RiscoRESUMO
OBJECTIVE: To compare the long-term effects of glucose-lowering medications (insulin glargine U-100, glimepiride, liraglutide, and sitagliptin) when added to metformin on insulin sensitivity and ß-cell function. RESEARCH DESIGN AND METHODS: In the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) cohort with type 2 diabetes (n = 4,801), HOMA2 was used to estimate insulin sensitivity (HOMA2-%S) and fasting ß-cell function (HOMA2-%B) at baseline and 1, 3, and 5 years on treatment. Oral glucose tolerance test ß-cell responses (C-peptide index [CPI] and total C-peptide response [incremental C-peptide/incremental glucose over 120 min]) were evaluated at the same time points. These responses adjusted for HOMA2-%S in regression analysis provided estimates of ß-cell function. RESULTS: HOMA2-%S increased from baseline to year 1 with glargine and remained stable thereafter, while it did not change from baseline in the other treatment groups. HOMA2-%B and C-peptide responses were increased to variable degrees at year 1 in all groups but then declined progressively over time. At year 5, CPI was similar between liraglutide and sitagliptin, and higher for both than for glargine and glimepiride [0.80, 0.87, 0.74, and 0.64 (nmol/L)/(mg/dL) * 100, respectively; P < 0.001], while the total C-peptide response was greatest with liraglutide, followed in descending order by sitagliptin, glargine, and glimepiride [1.54, 1.25, 1.02, and 0.87 (nmol/L)/(mg/dL) * 100, respectively, P < 0.001]. After adjustment for HOMA2-%S to obtain an estimate of ß-cell function, the nature of the change in ß-cell responses reflected those in ß-cell function. CONCLUSIONS: The differential long-term effects on insulin sensitivity and ß-cell function of four different glucose-lowering medications when added to metformin highlight the importance of the loss of ß-cell function in the progression of type 2 diabetes.
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Diabetes Mellitus Tipo 2 , Resistência à Insulina , Metformina , Compostos de Sulfonilureia , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insulina Glargina/uso terapêutico , Hipoglicemiantes/uso terapêutico , Glucose/uso terapêutico , Liraglutida/farmacologia , Liraglutida/uso terapêutico , Resistência à Insulina/fisiologia , Peptídeo C , Glicemia , Metformina/uso terapêutico , Fosfato de Sitagliptina/uso terapêuticoRESUMO
BACKGROUND: Combining multimodal lifestyle interventions and disease-modifying drugs (novel or repurposed) could provide novel precision approaches to prevent cognitive impairment. Metformin is a promising candidate in view of the well-established link between type 2 diabetes (T2D) and Alzheimer's Disease and emerging evidence of its potential neuro-protective effects (e.g. vascular, metabolic, anti-senescence). MET-FINGER aims to test a FINGER 2.0 multimodal intervention, combining an updated FINGER multidomain lifestyle intervention with metformin, where appropriate, in an APOE ε4-enriched population of older adults (60-79 years) at increased risk of dementia. METHODS: MET-FINGER is an international randomised, controlled, parallel-group, phase-IIb proof-of-concept clinical trial, where metformin is included through a trial-within-trial design. 600 participants will be recruited at three sites (UK, Finland, Sweden). Participants at increased risk of dementia based on vascular risk factors and cognitive screening, will be first randomised to the FINGER 2.0 intervention (lifestyle + metformin if eligible; active arm) or to receive regular health advice (control arm). Participants allocated to the FINGER 2.0 intervention group at risk indicators of T2D will be additionally randomised to receive metformin (2000 mg/day or 1000 mg/day) or placebo. The study duration is 2 years. The changes in global cognition (primary outcome, using a Neuropsychological Test Battery), memory, executive function, and processing speed cognitive domains; functional status; lifestyle, vascular, metabolic, and other dementia-related risk factors (secondary outcomes), will be compared between the FINGER 2.0 intervention and the control arm. The feasibility, potential interaction (between-groups differences in healthy lifestyle changes), and disease-modifying effects of the lifestyle-metformin combination will be exploratory outcomes. The lifestyle intervention is adapted from the original FINGER trial (diet, physical activity, cognitive training, monitoring of cardiovascular/metabolic risk factors, social interaction) to be consistently delivered in three countries. Metformin is administered as Glucophage®XR/SR 500, (500 mg oral tablets). The metformin/placebo treatment will be double blinded. CONCLUSION: MET-FINGER is the first trial combining a multimodal lifestyle intervention with a putative repurposed disease-modifying drug for cognitive impairment prevention. Although preliminary, its findings will provide crucial information for innovative precision prevention strategies and form the basis for a larger phase-III trial design and future research in this field. TRIAL REGISTRATION: ClinicalTrials.gov (NCT05109169).
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Doença de Alzheimer , Disfunção Cognitiva , Diabetes Mellitus Tipo 2 , Metformina , Idoso , Humanos , Disfunção Cognitiva/prevenção & controle , Disfunção Cognitiva/epidemiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Reposicionamento de Medicamentos , Estilo de Vida , Metformina/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: Retinal vascular network changes may reflect the integrity of the cerebral microcirculation, and may be associated with cognitive impairment. METHODS: Associations of retinal vascular measures with cognitive function and MRI biomarkers were examined amongst Multi-Ethnic Study of Atherosclerosis (MESA) participants in North Carolina who had gradable retinal photographs at Exams 2 (2002 to 2004, n = 313) and 5 (2010 to 2012, n = 306), and detailed cognitive testing and MRI at Exam 6 (2016 to 2018). RESULTS: After adjustment for covariates and multiple comparisons, greater arteriolar fractal dimension (FD) at Exam 2 was associated with less isotropic free water of gray matter regions (ß = -0.0005, SE = 0.0024, p = 0.01) at Exam 6, while greater arteriolar FD at Exam 5 was associated with greater gray matter cortical volume (in mm3 , ß = 5458, SE = 20.17, p = 0.04) at Exam 6. CONCLUSION: Greater arteriolar FD, reflecting greater complexity of the branching pattern of the retinal arteries, is associated with MRI biomarkers indicative of less neuroinflammation and neurodegeneration.
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Aterosclerose , Fractais , Humanos , Vasos Retinianos/diagnóstico por imagem , Aterosclerose/diagnóstico por imagem , Neuroimagem , Biomarcadores , CogniçãoRESUMO
Background Our aim was to investigate the association of coronary artery calcium (CAC) with cognitive function in adults with impaired glucose tolerance or type 2 diabetes. Methods and Results The Diabetes Prevention Program was a randomized controlled trial comparing an intensive lifestyle intervention, metformin, or placebo for prevention of type 2 diabetes among patients with prediabetes. After 3 years, intensive lifestyle intervention and placebo were stopped, the metformin arm was unmasked, and participants continued in the DPPOS (Diabetes Prevention Program Outcomes Study). Approximately 14 years after randomization (Y14), CAC (Agatston score) was assessed with computed tomography, and cognitive performance was assessed with the Spanish English Verbal Learning Test (SEVLT) and Digit Symbol Substitution Test. SEVLT and Digit Symbol Substitution Test were reassessed 5 years later (Y19) along with the Modified Mini-Mental State Exam. We examined cross-sectional and longitudinal associations between CAC and cognition among 1931 participants using linear and logistic regression. In unadjusted analyses, compared with no calcification, CAC score >300 was associated with decreased performance on all cognitive tests at Y14 in both sexes. Additionally, CAC >300 was associated with a greater 5-year decline in SEVLT Immediate Recall in both sexes and SEVLT Delayed Recall in women. After adjustment for demographic, genetic, metabolic, vascular, and behavioral covariates, CAC score >300 remained associated with greater decline in only SEVLT Delayed Recall in women. Conclusions In women with prediabetes or diabetes, CAC >300, compared with no calcification, was independently associated with greater decline in verbal memory. Registration information clinicaltrials.gov. Identifier: NCT00038727.
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Calcinose , Disfunção Cognitiva , Doença da Artéria Coronariana , Diabetes Mellitus Tipo 2 , Metformina , Estado Pré-Diabético , Calcificação Vascular , Masculino , Adulto , Humanos , Feminino , Diabetes Mellitus Tipo 2/complicações , Estado Pré-Diabético/complicações , Cálcio , Vasos Coronários , Estudos Transversais , Metformina/uso terapêutico , Disfunção Cognitiva/complicações , Calcinose/complicações , Cálcio da Dieta , Calcificação Vascular/complicações , Fatores de RiscoRESUMO
Importance: New York State's Medicaid managed long-term care (MLTC) program expanded access to home- and community-based services, providing an alternative to nursing home care for people with dementia. Between 2012 and 2015, the state implemented mandatory MLTC for dual Medicare and Medicaid enrollees requiring more than 120 days of community-based long-term care. Objective: To evaluate changes in nursing home use among older adults with dementia following MLTC implementation. Design, Setting, and Participants: This cohort study used longitudinal data from January 1, 2011, to December 31, 2019, from the Minimum Data Set and Medicare administrative data. The study sample included New York State Medicare beneficiaries 65 years and older with dementia. New York City residents were excluded due to insufficient pre-study period data. Data were analyzed from January 1, 2011, to December 31, 2019. Exposure: Mandatory MLTC enrollment. Main Outcomes and Measures: Longitudinal models were used to evaluate changes in annual days of nursing home use following the staggered implementation of MLTC across 13 regions of the state. Two models were estimated: (1) a logistic regression model for any nursing home use in a given year and (2) a linear regression model of total nursing home days, conditional on any nursing home use. Models included annual event-time indicators specified as years until or since MLTC implementation. To capture MLTC effects for dual enrollees relative to non-dual Medicare enrollees, models included interaction terms for dual enrollment and event-time indicators. Results: This sample included 463â¯947 Medicare beneficiaries with dementia who lived in New York State between 2011 and 2019 (50.2% younger than 85 years; 64.4% women). Implementation of MLTC was associated with lower odds of nursing home use among dual enrollees, ranging from 8% lower odds 2 years post implementation (adjusted odds ratio, 0.92 [95% CI, 0.86-0.98]) to 24% lower odds 6 years post implementation (adjusted odds ratio, 0.76 [95% CI, 0.69-0.84]). Compared with a scenario of no MLTC, MLTC implementation was associated with an 8% reduction in annual days of nursing home use between 2013 and 2019 (mean, -5.6 [95% CI, -6.1 to -5.1] days per year). Conclusions and Relevance: The findings of this cohort study suggest that implementation of mandatory MLTC in New York State was associated with less nursing home use among dual enrollees with dementia and that MLTC may help prevent or delay nursing home placement among older adults with dementia.
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Demência , Medicaid , Humanos , Feminino , Idoso , Estados Unidos , Masculino , Medicare , Estudos de Coortes , Serviços de Saúde Comunitária , Casas de Saúde , Cidade de Nova Iorque , Demência/terapiaRESUMO
OBJECTIVE: This study explored the association of BMI and insulin sensitivity with cognitive performance in type 2 diabetes. METHODS: A cross-sectional analysis of data from the baseline assessment of the Glycemia Reduction Approaches in Diabetes: a Comparative Effectiveness Study (GRADE) was conducted. BMI was used as a surrogate of adiposity and the Matsuda index as the measure of insulin sensitivity. Cognitive tests included the Spanish English Verbal Learning Test, the Digit Symbol Substitution Test, and the letter and animal fluency tests. RESULTS: Cognitive assessments were completed by 5018 (99.4%) of 5047 participants aged 56.7 ± 10.0 years, of whom 36.4% were female. Higher BMI and lower insulin sensitivity were related to better performance on memory and verbal fluency tests. In models including BMI and insulin sensitivity simultaneously, only higher BMI was related to better cognitive performance. CONCLUSIONS: In this study, higher BMI and lower insulin sensitivity in type 2 diabetes were cross-sectionally associated with better cognitive performance. However, only higher BMI was related to cognitive performance when both BMI and insulin sensitivity were considered simultaneously. The causality and mechanisms for this association need to be determined in future studies.
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Diabetes Mellitus Tipo 2 , Resistência à Insulina , Feminino , Humanos , Masculino , Índice de Massa Corporal , Cognição , Estudos Transversais , Diabetes Mellitus Tipo 2/complicações , Pessoa de Meia-Idade , IdosoRESUMO
Importance: Little is known about structural brain changes in type 1 diabetes (T1D) and whether there are early manifestations of a neurodegenerative condition like Alzheimer disease (AD) or evidence of premature brain aging. Objective: To evaluate neuroimaging markers of brain age and AD-like atrophy in participants with T1D in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study, identify which brain regions are associated with the greatest changes in patients with T1D, and assess the association between cognition and brain aging indices. Design, Setting, and Participants: This cohort study leveraged data collected during the combined DCCT (randomized clinical trial, 1983-1993) and EDIC (observational study, 1994 to present) studies at 27 clinical centers in the US and Canada. A total of 416 eligible EDIC participants and 99 demographically similar adults without diabetes were enrolled in the magnetic resonance imaging (MRI) ancillary study, which reports cross-sectional data collected in 2018 to 2019 and relates it to factors measured longitudinally in DCCT/EDIC. Data analyses were performed between July 2020 and April 2022. Exposure: T1D diagnosis. Main Outcomes and Measures: Psychomotor and mental efficiency were evaluated using verbal fluency, digit symbol substitution test, trail making part B, and the grooved pegboard. Immediate memory scores were derived from the logical memory subtest of the Wechsler memory scale and the Wechsler digit symbol substitution test. MRI and machine learning indices were calculated to predict brain age and quantify AD-like atrophy. Results: This study included 416 EDIC participants with a median (range) age of 60 (44-74) years (87 of 416 [21%] were older than 65 years) and a median (range) diabetes duration of 37 (30-51) years. EDIC participants had consistently higher brain age values compared with controls without diabetes, indicative of approximately 6 additional years of brain aging (EDIC participants: ß, 6.16; SE, 0.71; control participants: ß, 1.04; SE, 0.04; P < .001). In contrast, AD regional atrophy was comparable between the 2 groups. Regions with atrophy in EDIC participants vs controls were observed mainly in the bilateral thalamus and putamen. Greater brain age was associated with lower psychomotor and mental efficiency among EDIC participants (ß, -0.04; SE, 0.01; P < .001), but not among controls. Conclusions and Relevance: The findings of this study suggest an increase in brain aging among individuals with T1D without any early signs of AD-related neurodegeneration. These increases were associated with reduced cognitive performance, but overall, the abnormal patterns seen in this sample were modest, even after a mean of 38 years with T1D.
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Doença de Alzheimer , Complicações do Diabetes , Diabetes Mellitus Tipo 1 , Humanos , Adulto , Pessoa de Meia-Idade , Criança , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/diagnóstico por imagem , Estudos de Coortes , Estudos Transversais , Encéfalo/diagnóstico por imagem , Doença de Alzheimer/complicações , Envelhecimento , AtrofiaRESUMO
Background: Subclinical cardiovascular disease (CVD) measures may reflect biological pathways that contribute to increased risk for coronary heart disease (CHD) events, stroke, and dementia beyond conventional risk scores. Methods: The Multi-Ethnic Study of Atherosclerosis (MESA) followed 6,814 participants (45-84 years of age) from baseline in 2000-2002 to 2018 over 6 clinical examinations and annual follow-up interviews. MESA baseline subclinical CVD procedures included: seated and supine blood pressure, coronary calcium scan, radial artery tonometry, and carotid ultrasound. Baseline subclinical CVD measures were transformed into z-scores before factor analysis to derive composite factor scores. Time to clinical event for all CVD, CHD, stroke and ICD code-based dementia events were modeled using Cox proportional hazards models reported as area under the curve (AUC) with 95% Confidence Intervals (95%CI) at 10 and 15 years of follow-up. All models included all factor scores together and adjustment for conventional risk scores for global CVD, stroke, and dementia. Results: After factor selection, 24 subclinical measures aggregated into four distinct factors representing: blood pressure, arteriosclerosis, atherosclerosis, and cardiac factors. Each factor significantly predicted time to CVD events and dementia at 10 and 15 years independent of each other and conventional risk scores. Subclinical vascular composites of arteriosclerosis and atherosclerosis best predicted time to clinical events of CVD, CHD, stroke, and dementia. These results were consistent across sex and racial and ethnic groups. Conclusions: Subclinical vascular composites of arteriosclerosis and atherosclerosis may be useful biomarkers to inform the vascular pathways contributing to events of CVD, CHD, stroke, and dementia.
RESUMO
OBJECTIVES: Unexpected lucidity is a phenomenon of scientific, clinical, and psychological relevance to health professionals, to those who experience it, and their relatives. This paper describes qualitative methods used to develop an informant-based measure of lucidity episodes. METHODS: The approach was refinement of the operationalization of the construct; review of seminal items, modification, and purification; and confirmation of the feasibility of reporting methodology. Modified focus groups were conducted with 20 staff and 10 family members using a web-based survey. Themes included reaction when hearing the term; words that come to mind; description of and first reaction to referenced or observed 'lucidity' events. Semi-structured cognitive interviews were conducted with 10 health professionals working with older adults with cognitive impairment. Data were extracted from Qualtrics or Microsoft 365 Word® for analysis using NVivo. RESULTS: Conceptual issues, as well as issues regarding comprehension, interpretation, clarity, semantics, and standardization of definitions derived from an external advisory board, focus groups and cognitive interviews informed items' modification, and resulted in the final lucidity measure. CONCLUSIONS: An obstacle to understanding the mechanisms and estimating the prevalence of lucid events among individuals with dementia and other neurological conditions is the scarcity of reliable and valid measures. The substantive and varied data gathered from multiple methods including the collaborative work of an External Advisory Board, modified focus groups with staff and family caregivers, and structured cognitive interviews with health professionals were central in creating the revised version of the lucidity measure.
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Disfunção Cognitiva , Demência , Humanos , Idoso , Cognição , Cuidadores , Grupos Focais , Demência/psicologiaRESUMO
Alzheimer's disease (AD) is defined by the presence of Amyloid-ß (Aß),tau, and neurodegeneration (ATN framework) in the human cerebral cortex. Yet, prior studies have suggested that Aß deposition can be associated with both cortical thinning and thickening. These contradictory results are attributed to small sample sizes, the presence versus absence of tau, and limited detectability in the earliest phase of protein deposition, which may begin in young adulthood and cannot be captured in studies enrolling only older subjects. In this study, we aimed to find the distinct and joint effects of Aß andtau on neurodegeneration during the progression from normal to abnormal stages of pathologies that remain elusive. We used18F-MK6240 and 18F-Florbetaben/18F-Florbetapir positron emission tomography (PET) and magnetic resonance imaging (MRI) to quantify tau, Aß, and cortical thickness in 590 participants ranging in age from 20 to 90. We performed multiple regression analyses to assess the distinct and joint effects of Aß and tau on cortical thickness using 590 healthy control (HC) and mild cognitive impairment (MCI) participants (141 young, 394 HC elderlies, 52 MCI). We showed thatin participants with normal levels of global Aßdeposition, Aß uptakewassignificantly associated with increasedcortical thickness regardless of tau (e.g., left entorhinal cortex with t > 3.241, p < 0.0013). The relationship between tau deposition and neurodegeneration was more complex: in participants with abnormal levels of global tau, tau uptake was associated with cortical thinning in several regions of the brain (e.g., left entorhinal with t < -2.80, p < 0.0096 and left insula with t-value < -4.284, p < 0.0001), as reported on prior neuroimaging and neuropathological studies. Surprisingly, in participants with normal levels of global tau, tau was found to be associated with cortical thickening. Moreover, in participants with abnormal levels of global Aßandtau, theresonancebetween them, defined as their correlation throughout the cortex, wasassociated strongly with cortical thinning even when controlling for a direct linear effect. We confirm prior findings of an association between Aß deposition and cortical thickening and suggest this may also be the case in the earliest stages of deposition in normal aging. We also illustrate that resonance between high levels of Aß and tau uptake is strongly associated with cortical thinning, emphasizing the effects of Aß/tau synergy inAD pathogenesis.